Brain histamine is produced from L-histidine in histamine neurons and controls various CNS functions. Although histidine was known as a precursor of histamine, the impact of oral histidine intake on brain histamine concentration and brain function has not been fully elucidated. Here, we aimed to elucidate the importance of histidine intake in the histaminergic nervous system and working memory in stressful conditions. First, we confirmed that sleep deprivation by water-floor (WF) stress in male mice increased histamine consumption and resulted in histamine depletion and impaired working memory. This memory impairment was rescued by intracerebroventricular injection of histidine, indicating that oral histidine intake could also improve memory function. Histidine intake increased extracellular histamine concentration around the prefrontal cortex (PFC) and the basal forebrain (BF), leading to a robust increase in the number of c-fos-positive cells around these areas. We also revealed that histidine supplementation alleviated impaired memory function induced by WF stress through histaminergic activation.
These results demonstrate that oral histidine intake replenishes brain histamine and leads to the recovery of impaired working memory induced by sleep deprivation through histaminergic activation.